Abstract: A primary mechanism of lentivirus persistence is the ability of these viruses to evolve in response to biological and immunological selective pressures with a remarkable array of genetic and antigenic variations that constitute a perpetual natural experiment in genetic engineering. A widely accepted paradigm of lentivirus evolution is that the rate of genetic variation is correlated directly with the levels of virus replication: the greater the viral replication, the more opportunities that exist for genetic modifications and selection of viral variants. To test this hypothesis directly, we examined the patterns of equine infectious anemia virus (EIAV) envelope variation during a 2.5-year period in experimentally infected ponies that differed markedly in clinical progression and in steady-state levels of viral replication as indicated by plasma virus genomic RNA assays. The results of these comprehensive studies revealed for the first time similar extents of envelope gp90 variation in persistently infected ponies regardless of the number of disease cycles (one to six) and viremia during chronic disease. The extent of envelope variation was also independent of the apparent steady-state levels of virus replication during long-term asymptomatic infection, varying from undetectable to 10(5) genomic RNA copies per ml of plasma. In addition, the data confirmed the evolution of distinct virus populations (genomic quasispecies) associated with sequential febrile episodes during acute and chronic EIA and demonstrated for the first time ongoing envelope variation during long-term asymptomatic infections. Finally, comparison of the rates of evolution of the previously defined EIAV gp90 variable domains demonstrated distinct differences in the rates of nucleotide and amino acid sequence variation, presumably reflecting differences in the ability of different envelope domains to respond to immune or other biological selection pressures. Thus, these data suggest that EIAV variation can be associated predominantly with ongoing low levels of virus replication and selection in target tissues, even in the absence of substantial levels of plasma viremia, and that envelope variation continues during all stages of persistent infection as the virus successfully avoids clearance by host defense mechanisms.
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The study examines the evolution of the equine infectious ania virus (EIAV) in ponies. The research focused on the correlation between the rate of genetic variation and the level of virus replication, and found that viral variation can occur irrespective of the number of disease cycles and viral replication levels.
Investigating Virus Evolution
The research involved studying the patterns of EIAV envelope variation in experimentally infected ponies over a period of 2.5 years.
The ponies chosen had significant differences in their clinical progression and levels of viral replication.
Findings on EIAV Envelope Variation
The study found that similar extents of envelope gp90 variation occurred in infected ponies regardless of the number of disease cycles (one to six) and viremia during chronic disease.
In addition, there seemed to be no relation between the extent of envelope variation and the steady-state levels of virus replication during long-term asymptomatic infection.
Recognizing Distinct Virus Populations and Envelope Variation
Through the study, distinct virus populations (genomic quasispecies) related to sequential febrile episodes during acute and chronic EIA were identified.
Ongoing envelope variation was found to occur even during long-term asymptomatic infections.
Comparing Rates of Evolution
When comparing the rates of evolution of the previously defined EIAV gp90 variable domains, the research revealed clear differences in the rates of nucleotide and amino acid sequence variation.
This possibly indicates the different capabilities of different envelope domains to respond to immune or other biological selection pressures.
Implications of the Study
From these findings, the study suggests that EIAV variation can occur predominantly with ongoing low levels of virus replication and selection, even when there are no large levels of plasma viremia.
Moreover, envelope variation is continued throughout the stages of persistent infection, which allows the virus to successfully evade clearance by the host’s defense mechanisms.
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
Craigo, J K
Issel, C J
Montelaro, R C
MeSH Terms
Acute Disease
Amino Acid Sequence
Animals
Base Sequence
Chronic Disease
DNA, Viral
Disease Progression
Equine Infectious Anemia / physiopathology
Equine Infectious Anemia / virology
Evolution, Molecular
Genetic Variation
Genome, Viral
Glycoproteins / classification
Glycoproteins / genetics
Horses
Infectious Anemia Virus, Equine / classification
Infectious Anemia Virus, Equine / genetics
Molecular Sequence Data
Phylogeny
Sequence Homology, Amino Acid
Time Factors
Viral Envelope Proteins / classification
Viral Envelope Proteins / genetics
Viremia / virology
Grant Funding
P41 RR006009 / NCRR NIH HHS
R01 AI025850 / NIAID NIH HHS
2 P41 RR06009 / NCRR NIH HHS
R01 AI25850 / NIAID NIH HHS
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